Tri-(cyclic-lower alkylene mercapto)-s-antimonous acids



Patented June 6, 1950 UNITED STATES PATENT OFFICE TRI- (CYCLIC-LOWER ALKYLENE MER- CAPTO)-S-ANTIMONOUS ACIDS Le Roy W. Clemence, Highland Park, and Marlin T. Lefller, Lake Blufi, Ill., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Application December 18, 1947, Serial No. 792,612

8 Claims. (Cl. 260-446) wherein R1, R2 and R3 are organic radicals, either the same or different, each containing at least eight carbon atoms. In the preferred compounds of the present invention R1, R2 and R3 are hydrocarbon radicals each containing 8 to 18 carbon atoms inclusive.

We have discovered that antimoni'al compounds characterized by the above formula are active chemotherapeutic agents. They are effective, for example, in the treatment of certain tropical parasitic diseases, such as schistosomiasis.

We have discovered that the compounds of the present invention have the property of being soluble in oils, such as the fatty oils. We have also discovered that administration of the compounds for application as medicaments is very practical in oil mediums of this type.

We have tested a large number of compounds according to the invention and have found that those in which the R1, R2 and R3 groups contain not less than 8 nor more than 18 carbon atoms have varyingdegrees of therapeutic activity in the treatment of schistosomiasis. We have further found that the compounds having the highest activity are those in which the R groups have from about 10 to 14 carbon atoms, with those containing about 12 carbon atoms apparently more or less superior.

The compounds of this invention may be resolved into three groupings. In the first group are the tri-(n-alkyl mercapto) S antimonous acids. These alkyl groups have from eight to eighteen carbon atoms. The second grouping is the tri- (w-cyclic-alkyl-mercapto) -S-antimonous acids. Group three has substituents similar to group two except that an alkyl chain and ether linkages exist in addition to the cyclic group.

The preparation of the compounds of the pres.- ent invention may be accomplished in several novel ways. One way which has been successful is to dissolve one mole proportion of antimony trihalide in an inert solvent bywarming. This so-v lution is filtered into an equal quantity of an inert solvent miscible with the first solvent and containing three-mole proportions of the suitable R- mercaptan where the B group represents an organic radical as indicated above. The resulting solution is distilled under vacuum until the solvents have been removed. The residual oil is placed in a vacuum dryer over but not in contact with solid sodium hydroxide until the hydrohalic acid has been removed. The general reaction of this process may be expressed as follows:

in which M is a cation selected from the group comprising hydrogen and alkali and alkaline earth metals, and a: is three divided by valence of M. In certain cases, it is possible to react the antimony trihalide directly with mercaptans or mercaptides of alkali or alkaline earth metals.

The term halide as used in referring to an antimony trihalide throughout the specification cedure otherwise identical with that employing the chloride or the bromide, except that the iodide is employed, has not succeeded in causing the reaction to take place. It remains for some modified procedure to be found to cause the iodide reaction to be initiated and to proceed to completion. As compared to the trichloride and the tribromide, however, the cost would be very unfavorable due to the much higher cost of the triiodide.

Some of the compounds of the present invention have no exact physical constants such as melting point, boiling point, etc. Antimony analyses, however, demonstrate the compounds to be substantially pure. Most of the compounds are oils at room temperature, but those containing the higher R groups are often waxy substances either immediately after formation or upon standing. As the products are of an oily or waxy nature, solid halides may be removed by filtration and hydrohalides may be removed by volatilization.

It is also possible to react the antimony trihalide with a mixture or blend of selected mercaptans or mercaptides in such a way that the resulting therapeutic product Will be an antimony compound containing substituted mercaptide groups in the approximate percentages present in the original blend but obviously may result in variable analyses for antimony. Certain mercaptans are commercially in the form of mixtures having various hydrocarbon groups. For example, dodecyl mercaptan may have present decyl and tetradecyl mercaptans. Such products are suitable for use if reasonably pure and if not too much of non-mercaptans impurity is present.

EXAMPLE I Tri- (n-dodecyZ-mercapto) -S-am'z'monous acid (Ii-C12H25S) 3Sb About 7.61 gms. (0.033 mole) of antimonous trichloride is dissolved in 75 cc. of chloroform by warming. This solution is filtered into a 75 cc. solution of chloroform containing 20.2 gms. (0.1 mole) of ndodecyl-mercaptan. The resulting solution is distilled'under vacuum until the chloroform has been removed.

The residual oil, which smells slightly of hydrochloric acid formed during the reaction, is placed in a vacuum dryer over solid sodium hydroxide until all of the hydrochloric acid has been removed. The product obtained is a clear, pale yellow oil which becomes a waxy solid on standing at room temperature. The compound may be further solidified by cooling. Upon solidification it may be recrystallized from heptane giving a compound having a melting point of 38-40 C.

EXAMPLE IA Also, by using 10.0 gms. (0.05 mole) of the mercaptan and 6.03'gms. (0.017 mole) of antimony tribromide andproceeding as in Example I the compound tri- (n-dodecyl-mercapto) -S-antimonous acid is prepared.

Among cyclic alkyl compounds which have been prepared are those with the alkyl chain having from one to ten carbon atoms. The preferred range of compounds includes those having from one to five carbon atoms because the compounds are relatively easier to prepare. The cyclic group may be varied; it may be partially or totally saturated; it may be heterocyclic, also, it may be substituted.

EXAMPLE II Tri- [,B- (naphthyZ-I) -ethyimercaptol -S -antimonous acid CH2CH2 S About 7.61 gms. (0.033 mole) of antimonous trichloride is dissolved in 75 cc. of chloroform by warming. This solution is filtered into a 50 cc. solution of chloroform containing 18.8 gms. (0.1 mole of c-(naphthyl-D-ethyl mercaptan. The resulting solution is distilled under vacuum until the chloroform has been removed.

The residual oil, which smells slightly of hydrochloric acid formed during the reaction, is placed in a vacuum dryer over solid sodium hydroxide until all of the hydrochloric acid has been removed. The product obtained is a clear, pale yellow oil which becomes a waxy solid on standing.

EXAMPLE HI Tri- [p- (cyclohexyl) -ethylmercaptol -S-antimonous acid H CHaCH2-S Hi H2 Ha Hz By substituting in either Examples I or II, 14.4 gms. (0.1 mole) of ,c-cyclohexyl) ethyl mercaptan the above" compound may be obtained. This product is isolated just as the products of Examples I and II are.

EXAMPLE IV T'ri- [w cycloherylamylmercapto] -,S'-'antimonous acid H CH:(CH2)!CH2S EXAMPLE V Tri- [w- (B-tetralyl) -batylmercaptol-S-antimonous acid omomomomp H2 In a manner analogous to Example -IV and using a solution of 7.61 gms. (0.033 mole) ofantimony trichloride in 50 cc. of chloroform and'a solution of 21.9 gms. (0.1 moleof w-(B-tetralyD- butylmercaptan the above compoundis obtained.

EXANIPLE VI Tri- [w-decalylbutylmercaptol s-a'n'tz'monous acid H H H:

V H H2 Hz H: 3

Using the same procedure as in Example IV but substituting 22.3 gms. (0.1'mole) of w-decalyL butylmercaptan dissolved in 50 cc. ofchloroform and repeating the use of 7.61 gms. (0.033.1'11018) of antimony trichloride, the above-compound is obtained.

Among other representative compounds which we haveprepared by the above process by substitution of the proper mercaptan are listed below:

Tfi- (R -m e rcapto) -S-antimnous acids rate that the temperature remains below 0 C. The mixture is next permitted to reach room temperature while being stirred. After standing' overnight it is heated to 100 C. for several hours. The mixture is then cooled and poured sb-s-R, into 1,000 cc. of ice and water with agitation. The heavy, oily layer is separatedand dissolved Antimony Content 3;, It; and R; Formula Theoretical Found Percent Percent n-Octyl- (11CaH11S):Sb 21. 9 20. 8 n-Decyl-. gfl-CwHflS-hSb 19. 0 l9. 7 n-CuHazS-hSb 17. 8 17. 0 l1-C14Hz9S):Sb, melting point 50-51 C 15. 0 J 14. 3 nC1uHnS);Sb, melting point ESL-52 C 14. 4 l3. 6 nC1aHa7S)aSb, melting point 5859 C 12. 4 11. 2 CaH5CH2CH2-S-)aSb I 22.8 20.9

B-(Z-PyridyD-ethyl- 22. 72 21. 4

OHzCHzS- N 3 B (p Diisobutyl phenoxyethoxy)- CH: 11.6 11.6'

ethyl- (IJ (CHzhC-CH: O 1 CH; (:JHQ Sb CH2 v 2)CHzCH2S- 3 The compounds used as intermediates in the synthesis of tri-[w-cyclohexylamylmercapto]-S- antimonous acid, tri-[w- (fl-tetralyl) -butylmercaptol-S-antimonous acid and tri-[w-decalylbutylmercaptol-S-antimonous acid are new in the art and have been preparedby the methods given below.

In general, the w-cyclic-alkyl alcohol is converted to the w-cyclic alkyl halide by means of a phosphorous halide or a hydrohalogen acid. This halide is reacted with thiourea to form the w-cyclicalky1 isothiuronium halide. This compound is hydrolyzed to the w-cyclic alkyl mercaptan by alkaline hydrolysis using a dilute base such as sodium hydroxide. Also, the B-(p-diisobutylphenoxyethoxy)-ethyl mercaptan used in making the last compound in the table may be prepared by the same synthesis. Namely, this involves converting the alcohol to the halide; reacting the halide with isothiourea and hydrolyzing this to the mercaptan.

Once having the mercaptan, the compounds of the invention may be prepared as described above.

In detail, these compounds may be prepared as follows:

EXAMPLE VII w-Cyclohexylamyl bromide OH:(OH:)a OHsBr H: Ha

B: About 227 gms. (1.33 mole) of cyclohexylamyl alcohol (prepared by the hydrogenation of ethylw-cyclohexyl valerate at a temperature of 250 C. under a pressure of 3,600 pounds per square times with water followed by a solution of sodium carbonate. After being rewashed with Water, the ether solution is dried over magnesium sulfate. the magnesium sulfate is removed by filtration, and the ether evaporated. When fractionated in vacuum the yield obtained boils between 89.5-90.5 C. at 1 mm. pressure.

EXAMPLE VIII To about 23.3 gms. (0.1 mole) of iii-cyclohexylamyl bromide (Example VII) is added a hot filtered solution of 7.6 gms. (0.1 mole) of thiourea in cc. of absolute alcohol containing a small amount of benzene as the denaturant (12A absolute alcohol). The mixture is refluxed for 36 hours, cooled, and stirred until the whole mass becomes a crystalline mush. The solid is filtered, washed with a little acetone and dried. After recrystallization of this material from boiling water, the compound has a melting point of -141 0.

EXAMPLE DC w-CycZohexylamg l mercaptan Ha H:

About 78 gms. (0.25 mole) of w-cyclohexylamyl .isothiuronium bromide (Example VIII) is added to a solution of 50 gms. (1.25 mole) oi sodium hydroxide dissolved in 325 cc. of water. The mixture is heated to boiling and refluxed for 10 minutes. It is then cooled quickly and made acid to Congo red by the addition of concentrated hydrochloric acid. This mixture is extracted with ether, the ether extract dried over-anhydrous sodium sulfate. 'The sodium sulfate is removed by filtration and the ether removed by evaporation. The residual oil is purified by vacuum fraction'al distillation. The pure fraction boils at 89.5 to 91*"0. at pressure. The compoundha's 'a refractive index or 114820 at 25 C'. when'eompared to the D"'"1ine of sodium.

EXAMPLE X w-TB-tetrdZy'l) butyl bromide In a manner analogous to that of Example VII but substituting w-(p-tetral'yl) butyl alcohol (prepared by hydrogenating ethyl w- (tetralyl) butyrate. This alcohol has a boiling point of 167 C. at mm. and a refractive index of 1.5391 at 25 C. as compared to the D line of sodium.) for wcyclohexylamyl alcohol; the above-mentioned compound is prepared. The w-(c-tetralyl) butyl bromide obtained has a boiling point of 147-8 C. at 1 mm. pressure and a refractive index of 1.5528 at 25 C. when compared to the D line of sodium.

EXAMPLE XI -w-D8CdlfljlbtLtZ/Z bromide In a manner analogous to Example VII but substituting w-dec'alyl butyl alcohol (prepared by hydrogenating ethyl w-decalylbutyrate. This alcohol has a boiling point of 148-9 C. at 0.5 mm. pressure and a refractive index of 1.4919 at 25 C. when compared to the D line of sodium.) for a w-cyclohexylamyl alcohol; the above mentioned compound is obtained. This w-decalylbutyl bromide has a boiling point of 121-3 C. and a refractive index of 15020 at 25 C. when-compared to the D line of'sodium.

EXAlVIPLE XII -w-(fi-tetralyb butyl isothiuronium bromide Hz N H onucmncm's-ttnn:

Hi H

By 'means of the process described in Example IX, the compound w-(e-tetra1yl) -butyl isothiuronium bromide (Example XII) may be converted to the above mercaptan. This-compound has a boiling point of 143 C. at 0.8 mm. pressure and "has a refractive index of 1.5569 at 25 C. when compared with the D line of sodium.

EXAMPLE XV w-Decalylbutyl mercaptan -C HaCHzCHgCHzSH Using the procedure described in Example IX, the compound w-decalylbutyl .isothiuronium bromide (Example XI-II) may be converted to the above-mentioned mercaptan. This compound, w-decalylbutyl mercaptan, has a boiling point of 124 C. at 0.5 mm. pressure.

The reference to the term halogen in the preparation of intermediates is intendedto include-the elements, chlorine, bromine and-iodine.

The compounds of the present invention may be incorporated into pharmaceutical vehicles, and since they are oil soluble, they may beeffectively administered in oil solutions. The solutions may be prepared by dissolving the compounds in fatty or vegetable oils such as peanut, olive or :almond oil, 'indesired concentrations. Concentrations of about 10 per cent .havebeen found to be satisfactory.

Others may readily adapt the invention for use under varying conditions'of service, by employing one or more of the novel features disclosed, or equivalents thereof. As at presentedvised with respectto the-apparent scope of our invention, we desire to claim'the following subject matter.

We claim:

1. Tri(w-cyc1ic-a1kyl .mercaptm-S-antimonous acids with the following formula:

.SR'X

SbSR-X sR-x I wherein X is a cyclic group and'R is a lower alkylene group containing .upto 10 carbonatoms inclusive and being characterized by a CHzCH'z group attached tothesulfur atom. g

2. The compound itrim-naphthyld)-ethylmercaptol-S-antimonous acid with the following-formula: i Y

3. The compound tri-[B-(cyclohexyl) -ethylmercapto] -S-a,ntimonous acid with the following formula:

H OHIUHi-S- 4. The compound tri-lw-cyclohexylamyl-mercaptol -S- antimonous acid with the formula:

5. The compound tri-[w-(p-tetralyl) -butylmercaptol -S-antimonous acid with the formula:

HzH

6. The compound tri- (w-decalylbutyhnercapto) -S-antimonous acid with the following 7. A tri-[w-(naphthyl) -lower alkyl-mercaptol- S-antimonous acid.

8. A tri- [w (cyclohexyD-lower alkyl-mercaptol -S-antimonous acid.

. LE ROY W. CLEMENCE.

MARLIN T. LEFFLER.

REFERENCES CITED The following references are of record in the 2Q file of this patent:

UNITED STATES PATENTS Number Name Date 1,561,535 Hahl Nov. 1'7, 1925 25 2,226,530 Brown et a1. Dec. 31, 1940 2,229,992 Schmidt Jan. 28, 1941 Certificate of Correction Patent No. 2,510,740

LE ROY W. CLEMENCE ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 5, line 75, strike out in ether, the ether solution is Washed several and insert the same after dissolved in column 6, line 7; I

and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the PatentQflice.

Signed and sealed this 12th day of September, A. D. 1950.

June 6, 1950 THOMAS F. MURPHY,

Assistant Gammz'ssz'oner of Patents. 

1. TRI(W-CYCLIC-ALKYL MERCAPTO) -S-ANTIMONOUS ACIDS WITH THE FOLLOWING FORMULA: 